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156 Results for Collaborations
Collaborations
Johnson & Johnson has provided Drs. Audrey Odom John and Paul Hruz at Washington University in St. Louis (WUSTL) with its Jump-stARter library to screen against Plasmodium falciparum, the most deadly species of malaria parasite. Drs. Odom John and Hruz have developed a novel platform to selectively screen compounds’ ability to inhibit parasite glucose transport.
Dr. Stephen Ghogomu at the University of Buea has identified two proteins as potential biomarkers for adult-stage onchocerciasis. To support his diagnostic development, Dr. Jose Gomez-Marquez and Dr. Kimberly Hamad Schifferli at the Massachusetts Institute of Technology (MIT) have shared Ampli Blocks, a platform for diagnostic development. Dr. Ghogomu will use these blocks as a platform to develop an onchocerciasis diagnostic device.
The Ampli Block kit includes a set of 40 different building blocks that enable lab workers around the world to assemble them in different ways to produce diagnostic devices. By supplementing the engineering of diagnostic development, Ampli Blocks allow researchers to focus on the biochemistry of detection and promote independent development of site-specific diagnostic devices.
Artemisinin combination therapy (ACT) is the standard of care in treating uncomplicated malaria, while newer synthetic endoperoxides like artefenomel are being actively studied in clinical trials. Adam Renslo, in the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF), is exploring artefenomel-like trioxolane analogs bearing a novel substitution pattern that may deliver improved physiochemical properties. To assist the Renslo Lab in driving this program toward clinical candidate selection, Medicines for Malaria Venture (MMV) is supporting the Renslo Lab in assessing the solubility, lipophilicity, and metabolic stability of frontrunner compounds using appropriate in vitro ADME assays. The resulting data will be a key factor in the selection of the best analogs for further in vivo evaluation. Given the extent of work and progress in the endoperoxide area, new compounds will only be of interest if their pharmacokinetics and potency support very low single dose potential with no alteration of parasite clearance between sensitive and resistant parasites. These early studies will help to assess the Renslo Lab compounds against this high bar.
Dr. Audrey Odom John (Washington University in St. Louis) and Dr. Cynthia Dowd (The George Washington University) identified an antimalarial drug candidate with a novel, parasite-specific target. The investigators have explored various solutions to improve the compound’s pharmacokinetic properties, including administration in a patch formulation. BVGH coordinated a call between Dr. Odom John, Dr. Dowd, and a Pfizer scientist with expertise in transdermal drug delivery to help assess the feasibility of this approach for the compound.
A Pfizer scientist with expertise in transdermal drug delivery shared advice on the feasibility of a transdermal delivery for the investigators’ antimalarial drug candidate and helped suggest next steps for development.
In an effort to develop novel drugs against Chagas disease, Dr. Artur Cordeiro at the Brazilian Biosciences National Laboratory (LNBio) has identified chemical scaffolds that have shown activity against two promising targets and efficacy against the parasite’s intracellular form. In order to identify additional inhibitors or novel chemical scaffolds with activity against both Trypanosoma cruzi enzymes, Dr. Cordeiro will be working with Novartis as part of their Facilitated Access to Screening Technologies (FAST) Lab program to screen several of Novartis’ proprietary compounds against these two targets to identify tool compounds for structure-based drug discovery.
Leishmaniasis is endemic in nearly 100 countries worldwide, and with treatment failure a growing problem, there is an urgent need for development of novel first-line agents. Dr. Edmund Ekuadzi, co-manager of the Kwame Nkrumah University of Science and Technology (KNUST) Central Laboratory and former Novartis Next Generation Scientist Program fellow, is exploring the anti-leishmanial properties of Ghanaian plants used in traditional medicines. He will receive training in bioassay-guided fractionation of plant extracts through the Wellcome Centre for Anti-Infectives Research (WCAIR) program at the University of Dundee to advance his drug discovery programs.
University of Dundee will be providing expertise on fractionation and synthesis of small molecule compounds, as well as a bioassay for the fractionation of plant extracts. University of Dundee will be hosting Dr. Ekuadzi for a three-month fellowship, beginning in June.
172 Results for Assets
Assets
The present invention relates to DNA sequences encoding merozoite antigen proteins of simian or simian-like species of Plasmodium suitable for use as vaccines against malarial infections in humans and animals. The invention also relates to recombinant DNA molecules that include such sequences and to cells transformed therewith.
The technology describes an exceptionally broad universe of novel naphthylisoquinoline alkaloid compounds, and methods of total synthesis thereof. These compounds have been shown to have potent in vitro activity against malaria parasites, including parasites that are highly resistant to available antimalarial drugs. These compounds have also been shown to have potent in vivo activity against malaria parasites in animal models. Pharmaceutical compositions comprising these compounds, as well as methods of using the compounds to treat or prevent a malarial infection of a host, are claimed.
NIH Internal Reference no E-200-1994/0-US-01, US Patent Application no 08/279,291, US Patent no 5,552,550; E-200-1994/0-US-02, US Patent Application no 08/674,362, US Patent no 5,763,613; E-200-1994/2-US-01, US Patent Application no 09/001,801, US Patent no 6,140,339; E-200-1994/2-US-08, US Patent Application no 09/527,002, US Patent no 6,331,630; E-200-1994/2-AU-04, AU Patent Application no 24496/99; E-200-1994/2-BR-05, BR Patent Application no 9814575-4; E-200-1994/2-CA-06, CA Patent Application no 2313487; E-200-1994/2-EP-07, EP Patent Application no 98966748.0, EP Patent no 1045837; E-200-1994/2-IN-03, IN Patent Application no 2000/00143/CHE; E-200-1994/1-AU-02, AU Patent Application no 31969/95, AU Patent no 709428; E-200-1994/1-CA-03, CA Patent Application no 2195647; E-200-1994/1-JP-05, JP Patent Application no 505844/1996; E-200-1994/1-EP-06, EP Patent Application no 03005979.4; follwoing EP patents share same EP Patent Application no 95928091.8 and same EP Patent no 0772595: E-200-1994/1-EP-04, E-200-1994/1-AT-07, E-200-1994/1-DE-08, E-200-1994/1-BE-09, E-200-1994/1-DK-10, E-200-1994/1-ES-11, E-200-1994/1-GR-12, E-200-1994/1-IT-13, E-200-1994/1-LU-14, E-200-1994/1-MC-15, E-200-1994/1-NL-16, E-200-1994/1-PT-17, E-200-1994/1-SE-18, E-200-1994/1-FR-19. The technology describes an exceptionally broad universe of novel naphthylisoquinoline alkaloid compounds, and methods of total synthesis thereof. These compounds have been shown to have potent in vitro activity against malaria parasites, including parasites that are highly resistant to available antimalarial drugs. These compounds have also been shown to have potent in vivo activity against malaria parasites in animal models. Pharmaceutical compositions comprising these compounds, as well as methods of using the compounds to treat or prevent a malarial infection of a host, are claimed.
ANTIMALARIAL NAPHTHYLISOQUINOLINE ALKALOIDS AND PHARMACEUTICAL COMPOSITIONS AND MEDICAL USES THEREOF
The subject technology are novel naphthylisoquinoline alkaloid compounds, and methods of total synthesis thereof. Representative examples of these compounds have been shown to have potent in vitro activity against malaria parasites, including parasites that are highly resistant to available antimalarial drugs. Representative examples have also been shown to have potent in vivo activity against malaria parasites in animal models. Pharmaceutical compositions comprising these compounds, as well as methods of using the compounds to treat or prevent a malarial infection of a host, are claimed. The relative structural simplicity of this class of compounds, and the ready synthetic access thereto, provide unprecedented opportunities for structure-activity relationship (SAR), lead-optimization and antimalarial drug development.
Malaria is endemic in many parts of the world, particularly in tropical regions such as Asia, Central America and South America. Recent estimates of the number of cases of malaria worldwide are between five hundred million and one billion. There are approximately two to three hundred million new cases of malaria each year and malaria causes a minimum of one million deaths each year. This invention relates to the identification and characterization of the binding specificity of BAEBL, a novel Plasmodium falciparum erythrocyte binding ligand that interacts with human erythrocytes in a sialic acid dependent manner. This novel Plasmodium falciparum erythrocyte binding ligand is unique and quite distinct from previously described Plasmodium falciparum erythrocyte binding proteins EBA-175. BAEBL may be used as a malaria vaccine to block human red cell recognition and invasion.
The class of compounds known as korupensamines exhibit in vitro and in vivo antimalarial activity and offer a potent new means for treating and controlling this devastating disease. As many as 2-3 million people worldwide die from malaria each year, and many more suffer from long-term chronic infection. The deadliest malarial parasites have become resistant to previously effective antimalarial drugs such as chloroquine and other clinically useful agents; therefore, effective new antimalarial drugs are urgently needed. These korupensamine compounds, which are isolated from a new species of the plant genus Ancistrocladus which is found in tropical Africa and southern and southeast Asia, effectively inhibit the growth, reproduction, and pathologic effects of a broad spectrum of Plasmodia parasites when given alone or in conjunction with previously available antimalarial agents. Licensees of this invention will be required to comport with all applicable federal and country-of-collection policies relating to biodiversity.
The invention provides a synthetic gene encoding an allelic fonn of non-glycosylat~d Plasmodium falciparum Apical Membrane Antigen 1 optimized for codon usage in Pichia pastoris (e.g., AMAI FVa and AMAI 3D7); the subsequent transfonnation of Pichia pastoris with this gene, the separate optimization for pH, temperature, growth rate, and media composition of reproducible, scalable, clinical grade fennentation conditions for the expressionof the products of the gene; a method of purification for de-lipidation to clinical grade purity of the products of the gene; and proof of efficacy of the purified protein products in in vitro growth inhibition assays and in vivo non-human primate challenge models.
Expression, Purification And Efficacy testing of Synthetic Plasmodium Falciparum Apical Membrane Antigen 1 Expressed in Pichia Pastoris Two recombinant forms of the malaria asexual blood stage antigen Apical Membrane Antigen 1 AMA1 were produced in Pichia pastoris using totally defined, synthetic medias and a fermentation methodology that has been reproducibly scaled over a 10-fold range to 60L. High levels of secreted recombinant protein were obtained 300mg/L secreted protein in the supernatant, and >50mg/L final purified bulk protein , and a purification strategy developed to remove Host cell-derived lipids. Highly purified forms of both types of AMA1 produced appear to produce antibodies in vivo in rabbits that block homologous parasites from invading red blood cells in vitro. The combination of the two allelic forms made appears potent at inducing antibodies capable of blocking the invasion of many heterologous parasite strains in vitro, suggesting that the combination of these two alleles of AMA1 will provide sufficient coverage from the diverse field populations of parasites. One of the two AMA1's, based on the FVO allelic variant of AMA1, was emulsified with complete and incomplete Freund's adjuvant. Vaccination of highly susceptible Aotus vociferansmonkeys with this formulation conferred significant protection from a subsequent lethal challenge with the virulent FVO Plasmodium falciparumparasite. Five of eight animals whose primary immune response was directed against AMA1 were completely protected. These two recombinant forms of AMA1 may be an effective malaria vaccine. The production and purification methodologies may be suitable to other therapeutic proteins where large-scale, inexpensive production methodologies are required.